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Horm Metab Res 2023; 55(08): 555-562
DOI: 10.1055/a-2108-9820
Original Article: Endocrine Research

CircRNA SCAR Improves High-Glucose-Induced Mitochondrial Dysfunction and Permeability Damage in Retinal Microvascular Endothelial Cells

Rong Wu
1   Jishou University Medical College, Jishou, China
,
Sheng Huang
2   Department of Ophthalmology, TongRen Municipal People’s Hospital, Tongren, China
,
Jin-feng Xie
1   Jishou University Medical College, Jishou, China
,
Nian-lian Wen
2   Department of Ophthalmology, TongRen Municipal People’s Hospital, Tongren, China
,
Min Wen
3   Zunyi Medical University, Zunyi, China
,
Su-e Zhong
2   Department of Ophthalmology, TongRen Municipal People’s Hospital, Tongren, China
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Abstract

This study was designed to assess the role and mechanism of circRNA SCAR in human retinal microvascular endothelial cells (hRMVECs) treated with high glucose. Quantitative real-time polymerase chain reaction (qRT-PCR) and cell counting kit 8 (CCK-8) were used to detect the effects of different concentrations of glucose on circRNA SCAR expression and cell proliferation in hRMVECs. Cell viability, levels of oxygen species (ROS), malondialdehyde (MDA) and adenosine triphosphate (ATP), as well as activities of antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) in the transfected hRMVECs in each group were detected using CCK-8 and their corresponding detection kits. Changes in mtDNA copy number in high-glucose-induced hRMVECs were observed by qRT-PCR. Additionally, western blot was applied to detect effect of overexpressing circRNA SCAR on the expression levels of mitochondrial function-related proteins (Drp1 and Fis1) and cell permeability-related proteins (claudin-5, occludin and ZO-1) in hRMVECs under high-glucose concentration. According to experimental results, high glucose significantly downregulated circRNA SCAR expression and inhibited cell proliferation in hRMVECs. Instead, overexpression of this circRNA SCAR promoted cell proliferation, reduced levels of ROS, MDA and ATP, and increased SOD and CAT activities in hRMVECs under high-glucose concentration. Also, circRNA SCAR overexpression reversed the high-glucose-induced decrease in mtDNA copy number as well as, high-glucose-induced upregulation of Drp1 and Fis1 protein expression and downregulation of claudin-5, occludin and ZO-1 protein expression in hRMVECs. In summary, circRNA SCAR promotes the proliferation of hRMVECs under high-glucose concentration, alleviates oxidative stress induced by high glucose, and improves mitochondrial function and permeability damage.

Key words

retinal microvascular endothelial cells - high glucose - mitochondrial dysfunction - circRNA SCAR


Publication History

Received: 11 January 2023

Accepted after revision: 01 June 2023

Article published online:
03 July 2023

© 2023. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Guariguata L, Whiting DR, Hambleton I. et al. Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract 2014; 103: 137-149
    CrossrefPubMedGoogle Scholar
  • 2 Jourdan T, Szanda G, Cinar R. et al. Developmental role of macrophage cannabinoid-1 receptor signaling in type 2 diabetes. Diabetes 2017; 66: 994-1007
    CrossrefPubMedGoogle Scholar
  • 3 Leasher JL, Bourne RR, Flaxman SR. et al. Global estimates on the number of people blind or visually impaired by diabetic retinopathy: a meta-analysis from 1990 to 2010. Diabetes Care 2016; 39: 1643-1649
    CrossrefPubMedGoogle Scholar
  • 4 Wong TY, Cheung CM, Larsen M. et al. Diabetic retinopathy. Nat Rev Dis Primers 2016; 2: 16012
    CrossrefPubMedGoogle Scholar
  • 5 Semba RD, Huang H, Lutty GA. et al. The role of O-GlcNAc signaling in the pathogenesis of diabetic retinopathy. Proteomics Clin Appl 2014; 8: 218-231
    CrossrefPubMedGoogle Scholar
  • 6 Zhang MY, Zhu L, Zheng X. et al. TGR5 Activation ameliorates mitochondrial homeostasis via regulating the PKCdelta/Drp1-HK2 signaling in diabetic retinopathy. Front Cell Dev Biol 2021; 9: 759421
    CrossrefPubMedGoogle Scholar
  • 7 Miller DJ, Cascio MA, Rosca MG. Diabetic retinopathy: the role of mitochondria in the neural retina and microvascular disease. Antioxidants (Basel) 2020; 9: 905
    CrossrefPubMedGoogle Scholar
  • 8 Ma Z, Wirstrom T, Borg LA. et al. Diabetes reduces beta-cell mitochondria and induces distinct morphological abnormalities, which are reproducible by high glucose in vitro with attendant dysfunction. Islets 2012; 4: 233-242
    CrossrefPubMedGoogle Scholar
  • 9 Li X, Zhang M, Zhou H. The morphological features and mitochondrial oxidative stress mechanism of the retinal neurons apoptosis in early diabetic rats. J Diabetes Res 2014; 2014: 678123
    PubMedGoogle Scholar
  • 10 Rudraraju M, Narayanan SP, Somanath PR. Regulation of blood-retinal barrier cell-junctions in diabetic retinopathy. Pharmacol Res 2020; 161: 105115
    CrossrefPubMedGoogle Scholar
  • 11 Felinski EA, Cox AE, Phillips BE, Antonetti DA. Glucocorticoids induce transactivation of tight junction genes occludin and claudin-5 in retinal endothelial cells via a novel cis-element. Exp Eye Res 2008; 86: 867-878
    CrossrefPubMedGoogle Scholar
  • 12 Jo DH, Yun JH, Cho CS. et al. Interaction between microglia and retinal pigment epithelial cells determines the integrity of outer blood-retinal barrier in diabetic retinopathy. Glia 2019; 67: 321-331
    CrossrefPubMedGoogle Scholar
  • 13 Leal EC, Martins J, Voabil P. et al. Calcium dobesilate inhibits the alterations in tight junction proteins and leukocyte adhesion to retinal endothelial cells induced by diabetes. Diabetes 2010; 59: 2637-2645
    CrossrefPubMedGoogle Scholar
  • 14 Tang L, Zhang C, Yang Q. et al. Melatonin maintains inner blood-retinal barrier via inhibition of p38/TXNIP/NF-kappaB pathway in diabetic retinopathy. J Cell Physiol 2021; 236: 5848-5864
    CrossrefPubMedGoogle Scholar
  • 15 Nicolet BP, Engels S, Aglialoro F. et al. Circular RNA expression in human hematopoietic cells is widespread and cell-type specific. Nucleic Acids Res 2018; 46: 8168-8180
    CrossrefPubMedGoogle Scholar
  • 16 He M, Wang W, Yu H. et al. Comparison of expression profiling of circular RNAs in vitreous humour between diabetic retinopathy and non-diabetes mellitus patients. Acta Diabetol 2020; 57: 479-489
    CrossrefPubMedGoogle Scholar
  • 17 Zhou HR, Kuang HY. Circular RNAs: Novel target of diabetic retinopathy. Rev Endocr Metab Disord 2021; 22: 205-216
    CrossrefPubMedGoogle Scholar
  • 18 Chang X, Zhu G, Cai Z. et al. miRNA, lncRNA and circRNA: Targeted molecules full of therapeutic prospects in the development of diabetic retinopathy. Front Endocrinol (Lausanne) 2021; 12: 771552
    CrossrefPubMedGoogle Scholar
  • 19 Guo N, Liu XF, Pant OP. et al. Circular RNAs: novel promising biomarkers in ocular diseases. Int J Med Sci 2019; 16: 513-518
    CrossrefPubMedGoogle Scholar
  • 20 Liu C, Yao MD, Li CP. et al. Silencing of circular RNA-ZNF609 ameliorates vascular endothelial dysfunction. Theranostics 2017; 7: 2863-2877
    CrossrefPubMedGoogle Scholar
  • 21 Zeng Q, Liu J. Silencing circ_0001879 inhibits the proliferation and migration of human retinal microvascular endothelial cells under high-glucose concentration via modulating miR-30-3p. Gene 2020; 760: 144992
    CrossrefPubMedGoogle Scholar
  • 22 Liu G, Zhou S, Li X. et al. Inhibition of hsa_circ_0002570 suppresses high-glucose-induced angiogenesis and inflammation in retinal microvascular endothelial cells through miR-1243/angiomotin axis. Cell Stress Chaperones 2020; 25: 767-777
    CrossrefPubMedGoogle Scholar
  • 23 Zhao Q, Liu J, Deng H. et al. Targeting mitochondria-located circRNA SCAR alleviates NASH via reducing mROS output. Cell 2020; 183: e22
    CrossrefPubMedGoogle Scholar
  • 24 Pandey D, Yevale A, Naha R. et al. Mitochondrial DNA copy number variation – a potential biomarker for early onset preeclampsia. Pregnancy Hypertens 2021; 23: 1-4
    CrossrefPubMedGoogle Scholar
  • 25 Adzraku SY, Wang G, Cao C. et al. Robo4 inhibits gamma radiation-induced permeability of a murine microvascular endothelial cell by regulating the junctions. Cell Mol Biol Lett 2023; 28: 2
    CrossrefPubMedGoogle Scholar
  • 26 Feng Y, Wang R, Xu J. et al. Hydrogen-rich saline prevents early neurovascular dysfunction resulting from inhibition of oxidative stress in STZ-diabetic rats. Curr Eye Res 2013; 38: 396-404
    CrossrefPubMedGoogle Scholar
  • 27 Wu MY, Yiang GT, Lai TT. et al. The oxidative stress and mitochondrial dysfunction during the pathogenesis of diabetic retinopathy. Oxid Med Cell Longev 2018; 3420187
    PubMedGoogle Scholar
  • 28 Naruse R, Suetsugu M, Terasawa T. et al. Oxidative stress and antioxidative potency are closely associated with diabetic retinopathy and nephropathy in patients with type 2 diabetes. Saudi Med J 2013; 34: 135-141
    PubMedGoogle Scholar
  • 29 Lu L, Lu Q, Chen W. et al. Vitamin D(3) protects against diabetic retinopathy by inhibiting high-glucose-induced activation of the ROS/TXNIP/NLRP3 inflammasome pathway. J Diabetes Res 2018; 8193523
    PubMedGoogle Scholar
  • 30 Fan Y, Qiao Y, Huang J. et al. Protective effects of panax notoginseng saponins against high glucose-induced oxidative injury in rat retinal capillary endothelial cells. Evid Based Complement Alternat Med 2016; 5326382
    PubMedGoogle Scholar
  • 31 Jeong HY, Kang JM, Jun HH. et al. Chloroquine and amodiaquine enhance AMPK phosphorylation and improve mitochondrial fragmentation in diabetic tubulopathy. Sci Rep 2018; 8: 8774
    CrossrefPubMedGoogle Scholar
  • 32 Chang JY, Yu F, Shi L. et al. Melatonin affects mitochondrial fission/fusion dynamics in the diabetic retina. J Diabetes Res 2019; 8463125
    PubMedGoogle Scholar
  • 33 Kim D, Sankaramoorthy A, Roy S. Downregulation of Drp1 and Fis1 inhibits mitochondrial fission and prevents high glucose-induced apoptosis in retinal endothelial cells. Cells 2020; 9: 1662
    CrossrefPubMedGoogle Scholar
  • 34 Stitt AW, Curtis TM, Chen M. et al. The progress in understanding and treatment of diabetic retinopathy. Prog Retin Eye Res 2016; 51: 156-186
    CrossrefPubMedGoogle Scholar